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Transforming Growth Factor β1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression

  • Zhao, Hongying (Department of Pharmacy, Zhejiang Provincial People's Hospital) ;
  • Zhang, Jun (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Shao, Haiyu (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Liu, Jianwen (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Jin, Mengran (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Chen, Jinping (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Huang, Yazeng (Department of Orthopedics, Zhejiang Provincial People's Hospital)
  • Received : 2016.12.12
  • Accepted : 2017.02.22
  • Published : 2017.03.31

Abstract

Transforming growth factor ${\beta}1$ $(TGF{\beta}1)/Smad4$ signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through $TGF{\beta}1/Smad4$ signaling. Here, we present that $TGF{\beta}1$ elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR-155 induced by $TGF{\beta}1$. The results of luciferase reporter experiments and ChIP assays demonstrated that $TGF{\beta}1$ promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the $TGF{\beta}1/Smad4$ pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the $TGF{\beta}1$-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that $TGF{\beta}1/Smad4$ signaling affects osteoclast differentiation by regulation of miR-155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise.

Keywords

References

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